Cardiovascular Research

Cardiovascular Research 1997 34(1):73-80; doi:10.1016/S0008-6363(97)00036-9
© 1997 by European Society of Cardiology

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Schotborgh, C. E Articles by Wilde, A. A.M Search for Related Content PubMed PubMed Citation Articles by Schotborgh, C. E Articles by Wilde, A. A.M Social Bookmarking          What's this?

Copyright © 1997, European Society of Cardiology

Sulfonylurea derivatives in cardiovascular research and in cardiovascular patients

Carl E Schotborgh^a and Arthur A.M Wilde^a,b,*

^aDepartment of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, PO BOX 22700, 1100 DE Amsterdam, Netherlands
^bThe Heart-Lung Institute, University of Utrecht, Utrecht, Netherlands

^* Corresponding author. Tel.: +31 20 5663265; fax: +31 20 6975458.

Received 28 October 1996; accepted 14 January 1997

	Abstract

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). In the β-cell sulfonylureas act by blocking ATP-sensitive potassium channels (K.ATP channels). In several organ systems, including the cardiovascular system, sulfonylurea receptors and functional K.ATP channels have been identified. In the heart their role is not clear; an endogenous cardioprotective effect has been suggested. There is no doubt that K.ATP channels are effectively blocked by sulfonylureas. In the last decade sulfonylureas have been widely used as a pharmacological tool in experimental (cardiac) research. Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. However, other membrane currents are affected as well. In addition, myocardial metabolism is modified by sulfonylurea pretreatment. Hence, it should seriously be questioned whether these drugs are suitable in assessing involvement of cardiac K.ATP channels in, for example, ischemia-related events. The detrimental effects of sulfonylureas in experimental studies on myocardial ischemia have led to speculation whether the widespread use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease, should be reconsidered. However, a review of the clinical literature reveals that the most consistent finding is a lower incidence of ventricular arrhythmias associated with the use of glibenclamide, while no excess mortality has been shown for this agent in NIDDM with ischemic heart disease. Despite some direct effects on systemic and coronary vasculature, there are, at present, no firm clinical data on the basis of which sulfonylurea derivatives should be withheld from the cardiac patient.

KEYWORDS Sulfonylureas; Diabetes; Potassium channel, ATP-sensitive; Arrhythmias; Myocardial infarction; Myocardial ischemia

	1 Introduction

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). The mode of action of sulfonylureas on the β-cell has been elucidated and involves blockade of the ATP-sensitive potassium channels (K.ATP channels). The β-cell sulfonylurea receptor has been purified and cloned [1]. In itself the sulfonylurea receptor (named SUR1) does not possess ion-conducting properties, but together with an inwardly rectifying K⁺ channel (called Kir 6.2) it forms K⁺ channels with characteristics closely resembling functional pancreatic K.ATP channels [2]. Sulfonylurea receptors and functional K.ATP channels have been identified in several organ systems and their role and function in physiological and pathophysiological states has been described in many of them. In mitochondrial membranes of various tissues, including myocardium, K.ATP channels are also expressed [3–5]. On the molecular level a second type of (sarcolemmal) sulfonylurea receptor, designated SUR2, has been identified, with the highest expression levels in cardiac and skeletal muscle [6, 7]. A further subdivision has been described with the demonstration of a SUR2 subtype, designated SUR2A, exclusively expressed in heart and skeletal muscle and SUR2B, ubiquitously expressed in these and other extrapancreatic tissues [7, 8]. In situ hybridization of the latter subtype shows specific staining in the vascular structures of these tissues and for example in the muscularis layer of intestine [7]. In analogy with SUR1, co-expression of SUR2A and SUR2B with Kir 6.2 reconstitutes functional K.ATP channels of respectively the cardiac and skeletal type [6]and the smooth muscle type [8].

In general, K.ATP channels couple the metabolic state of the cell to its electrical activity. Thus, in the β-cell a regulatory role in determining insulin secretion has been established. In systemic and coronary vasculature, K.ATP channels are involved in the regulation of vascular tone [9]. In neurons, K.ATP channels can modify neurotransmitter release. However, in myocardial tissue the role is not clear; an endogenous protective role has been suggested.

K.ATP channels are effectively blocked by sulfonylureas. This property has prompted many basic scientists to use representatives of this group, most often glibenclamide, as a pharmacological tool in experimental research. Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. Other effects of sulfonylurea derivatives have been described as well but are seldom considered to play a role. This review aims, in the first place, to address whether all sulfonylurea effects are indeed to be explained by blockade of K.ATP channels.

Opening of myocardial K.ATP channels is cardioprotective, as is expressed in different functional and metabolic variables [10]. Sulfonylureas consistently counteract the beneficial effects of K.ATP channel openers (see Ref. [10]for review). In the absence of openers of K.ATP channels sulfonylureas may even exert deleterious effects on ischemic hearts: for example, in terms of reduced time before ischemic contracture develops [11, 12], increased infarct size [13], more stunning [11, 14], or prevention of preconditioning [15]. However, ischemia-related arrhythmias might be prevented by sulfonylurea pretreatment [16]. The deleterious effects of sulfonylureas have led to speculation whether the widespread use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease as well, should be reconsidered [15–17]. In addition to the critical assessment of their mechanism of action, relevant clinical data with respect to these postulated deleterious effects will be discussed.

	2 Effects on membrane currents

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
There can be no doubt that sulfonylurea derivatives effectively block myocardial K.ATP channels. The most widely used representative glibenclamide (glyburide) is one of the most potent sulfonylureas [18]. Clinically, in patients on glibenclamide a wide concentration range is encountered (0–1.5 µM/l; mean 0.5 µM/l) [19]. In vitro experiments on isolated guinea-pig and rat ventricular myocytes revealed that the efficacy of glibenclamide-induced inhibition of myocardial K.ATP channels is, compared to pancreatic β-cells, relatively low with a half-maximal inhibition concentration (IC₅₀) in the order of 5–10 µM [20, 21]. Although lower values for cardiac K.ATP channels have been reported as well [22], the affinity for pancreatic K.ATP channels is presumably 3 orders of magnitude higher [15, 18, 23, 24]. In line with these findings are the functional characteristics, including a higher affinity for glibenclamide in the same order of magnitude of SUR1 as of SUR2 [6]. Of particular relevance to the question whether myocardial K.ATP channel block is involved in the sulfonylurea-related deleterious effects is the observation that its efficacy to block the channel is increased by a reduction in pH [25]and is reduced after prolonged metabolic stress [20, 26].

K.ATP channels are not the only cardiac ionic channels inhibited by sulfonylureas. Recently, glibenclamide has been demonstrated to block the cAMP-activated chloride conductance (I_{Cl, cAMP}) [27]. The Hill coefficient for the effect on I_{Cl, cAMP} and on K.ATP channels is roughly similar, but the effective concentration range is considerably higher (half-maximal inhibition of I_{Cl, cAMP} ±30 µM [27]compared to 5–10 µM for half-maximal inhibition of K.ATP channels) (see above). Glibenclamide also blocks the cystic fibrosis transmembrane conductance regulator, another chloride channel, expressed in the heart with unknown function. The blocking action was irreversible with half-maximal inhibition in a concentration range comparable to affect I_{Cl, cAMP} [28]. It is not known whether factors pertinent to ischemia modify the glibenclamide sensitivity of these currents.

In non-cardiac tissue effects on other ion channels/currents have been described. Whereas in pancreatic β-cells sulfonylureas seem to be rather specific, with no effects at relevant dosages on other K⁺ channels [29], glibenclamide has been shown to inhibit a voltage-gated, Ca²⁺- and ATP-independent K⁺ current in the human neuroblastoma cell line SH-SY5Y (cells expressing several properties of noradrenergic neurons) [30]. In vascular smooth muscle cells glibenclamide (10 µM) has been shown to modulate the L-type Ca²⁺ channel current (both an increase and a decrease have been described, depending on the presence of the agonist BAY k-8644) [31]and to abolish, at the single channel level, the potassium channel opener-induced increase in the Ca²⁺-activated K⁺ channel [32]. In contrast, in isolated smooth muscle cells from rabbit portal vein glibenclamide did not affect the Ca²⁺-activated K⁺ channel [33]. In the same preparation glibenclamide inhibited the potassium channel opener-induced block of the oscillatory outward current [33]. This current is believed to be elicited by Ca²⁺ release from an intracellular store. The modulating effects of both the potassium channel opener pinacidil and glibenclamide suggest an effect on the kinetics of calcium release from these stores, which putatively represent the sarcoplasmic reticulum (SR). A similar conclusion has been reached by Chopra et al. who described a direct action of K.ATP channel modulators (including glibenclamide in concentrations >1 µM) on intracellular calcium stores in cultured airway smooth muscle of the rabbit [34]. Indeed, in skeletal muscle Ca²⁺ transport across the SR membrane is influenced by the state of K⁺ channels in the SR membrane [35]. K.ATP channels may be involved in this process.

	3 Effects on myocardial energy metabolism

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
Sulfonylureas affect myocardial energy metabolism. In aerobic rat hearts tolbutamide (in clinically relevant dosages) markedly stimulated glycogenolysis, glucose uptake and utilization and at the same time decreased fatty acid metabolism [36, 37]. The latter effect is due to direct inhibition of mitochondrial carnitine palmitoyltransferase, which is the key regulatory enzyme in fatty acid oxidation [38]. Alternatively, it may be speculated that blockade of mitochondrial K.ATP channels, with, compared to the sarcolemmal K.ATP channel, roughly similar affinity for sulfonylureas [4], is involved. As a result of stimulation of anaerobic glycolysis lactate production is increased, prior to any metabolic challenge [39, 40], and within 30 min glycogen levels may decrease by 30% [36, 37]. Due to these effects the contribution of glucose metabolism to ATP synthesis is greatly enhanced by tolbutamide [36, 37]. These effects, which are independent of insulin, are even more pronounced in diabetic hearts [37].

Observations that lactate production is inhibited during myocardial hypoxia [20]and myocardial ischemia [41]may reflect the reduced glycogen content prior to the experimental event.

	4 Impact on sulfonylurea action during metabolic inhibition

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
Glibenclamide-sensitive effects during metabolic inhibition include hypoxia- and ischemia-related action potential shortening, a rise in the extracellular potassium concentration ([K⁺]_o), a decrease in incidence of arrhythmias and the occurrence of preconditioning. The question now to address is whether it is possible that the sulfonylurea-induced effects on membrane currents other than the K.ATP channel or on myocardial glucose and free fatty acid metabolism are of any relevance to these effects. It may be argued that the relatively high concentrations needed to affect other currents preclude any non-K.ATP channel mediated effect. However, as mentioned before, with regard to the blocking efficacy of glibenclamide, it has been shown that intracellular pH sensitizes the channel to glibenclamide [25]. Similar effects might be present for any other sulfonylurea-mediated effect.

Particularly the shortening of the action potential and the increased K⁺ efflux are widely believed to result from hypoxia/ischemia-induced activation of K.ATP channels. This belief is almost exclusively based on the sulfonylurea sensitivity of these phenomena (see Refs. [16]and [42]). However, for example, with regard to the hypoxia-induced action potential shortening a variety of other currents might be involved, including I_{Cl, cAMP} as has been suggested previously [43]. Indeed, modulation of the extracellular chloride concentration and addition of chloride channel blockers (which are devoid of any effect on the K.ATP channel current) attenuate the early hypoxia-induced shortening of the action potential [44]. Hence, potentially the glibenclamide-induced blockade of I_{Cl, cAMP} may be involved in the attenuation of the hypoxia-related action potential shortening. The observation that the forskolin-induced shortening of the action potential is reversed by glibenclamide [27]corroborates this suggestion. The 3–6-fold difference in effective blocking concentration would preclude glibenclamide-induced block of I_{Cl, cAMP} being involved, but these values have been obtained in normoxic conditions. Although in later stages of metabolic deprivation the glibenclamide K.ATP channel block becomes less efficient [20, 26], no information is available on the blocking efficacy of other currents in similar conditions. We have previously noted that the observed time-delay for the channel to open in response to hypoxia [45], ischemia [46]or metabolic inhibition [47]is indeed difficult to reconcile with involvement of K.ATP channels in early action potential shortening [42].

In addition to theoretical considerations precluding a causative role for any K⁺ channel in determining increased K⁺ efflux, the latter arguments also hold for a potential role of K.ATP channels in explaining increased K⁺ efflux [42]. Further, the observation that glibenclamide might prevent hypoxia-induced K⁺ efflux by ±50%, which occurred in the absence of any change in action potential duration, also suggests that the sulfonylurea effect on K⁺ efflux is not related to K.ATP channels [48]. Pivotal to an alternative explanation for the sulfonylurea-induced effects on K⁺ accumulation might be the reduced levels of glycogen after pretreatment with sulfonylurea derivatives (see above). Such an effect will reduce glycolytic activity during the subsequent ischemic episode. This may result in less lactate production and in less intracellular acidification. Attenuation of intracellular acidification has been shown to be associated with less K⁺ accumulation [49]. Indeed, ischemia-induced [41]and hypoxia-induced lactate efflux [20]has been reported to be attenuated after glibenclamide pretreatment and we have observed an inverse linear relationship between the pre-ischemic lactate production by glibenclamide and the effect on extracellular potassium [Wilde et al., unpublished observations]. In addition, ³P-nuclear magnetic resonance spectroscopy during global ischemia in glycogen-depleted hearts (by other means, including which preconditioning) revealed less intracellular acidification than in control hearts [50, 51]. Extracellular acidification is not affected by glibenclamide in a variety of species where it does attenuate the ischemia-induced early rise in extracellular potassium [40], but this might well be a too crude measure for (anaerobic) glycolytic activity. Lactate has been shown to reduce action potential duration [52], which in itself may involve K.ATP channel activation [53]. Hence, the sulfonylurea-induced decrease in lactate efflux may serve as an alternative explanation for the related attenuation of action potential shortening.

The favorable effects of sulfonylureas on the arrhythmias during acute ischemia may relate to attenuation of the action potential shortening and the attenuation of the rise in [K⁺]_o. Particularly slowing of conduction, which is closely related to [K⁺]_o, is considered to play a key role in arrhythmogenesis in early ischemia.

With regard to preconditioning, two sulfonylurea-induced effects can be regarded as seriously confounding factors in explaining the modulatory effects of preconditioning: (1) the effects on metabolism discussed above and (2) the possible modulation of adenosine release, which seems to be a critical mediator of preconditioning. In general, preconditioning, which also leads to reduced glycogen content prior to the index ischemic period, is abolished by sulfonylureas (see Ref. [10]). Pre-ischemic reduction in glycogen content protects the heart from subsequent prolonged ischemia, in terms of myocardial injury (i.e., preconditioning) [54]. However, the concomitant sulfonylurea-induced prolonged action potential during ischemia may outweigh this effect and therefore not lead to attenuation of ischemic damage. Finally, glibenclamide has been shown to influence adenosine release. Experimental results are controversial; ischemia-related adenosine release in rabbits was not influenced by glibenclamide [55], but in rats the 5'-nucleotidase-mediated adenosine release was reduced by glibenclamide (in a concentration-dependent manner; EC₅₀ 10 µM) [56]. Because the adenosine release during ischemia invoked in the occurrence of preconditioning is mediated by the enzyme 5'-nucleotidase [57], any sulfonylurea effect on this pathway will have an impact on preconditioning.

In summary, in addition to blocking K.ATP channels there are many other effects of sulphonylureas. Since these effects might have impact on, probably all, ischemia-related events, the suitability of these drugs for assessment of involvement of cardiac K.ATP channels has been seriously questioned. Careful selection of the concentration might provide useful information. However, in the absence of relevant data on, for example, the blocking efficacy of glibenclamide on other currents in pathophysiological conditions, the statement that sulfonylureas cannot be used at all to serve this purpose might even be correct. Likewise, the use of glibenclamide to prove involvement of K.ATP channels in vascular smooth muscle has been questioned [58].

	5 NIDDM, sulfonylurea derivatives and cardiac disease

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
NIDDM patients are at increased risk of cardiovascular morbidity and mortality [59, 60]. In these patients sulfonylureas have always been the cornerstone of oral therapy [61], despite the early report of the University Group Diabetes Program which suggested an association between tolbutamide therapy and an increased risk of cardiovascular mortality [62]. However, shortly after its appearance this report became extensively criticized for methodological and statistical reasons [63–65]. The results of 7 other epidemiological studies performed in the 1970s were contradictory and not conclusive either [66]. Later Rytter et al. retrospectively compared patients with IDDM to those with NIDDM with respect to the prevalence and mortality of acute myocardial infarction [60]. They found a significantly higher mortality rate from acute myocardial infarction in NIDDM patients treated with oral hypoglycemic agents than in NIDDM patients treated with insulin (50 vs 9.1%; distribution of hypoglycemic agents not specified). This difference could not be explained by better in-hospital metabolic control in the insulin-treated patients. However, the pre-hospital metabolic state, a determinant of outcome in this study, was not reported for the two groups [60]. In another analysis of diabetic patients presenting with myocardial infarction, sulfonylurea treatment did not influence hospital outcome in terms of morbidity (pump failure) and mortality [67]. In this study prior metabolic control, assessed by glycosylated glucose, did not predict outcome either. Finally, Ulvenstam et al. reported on the long-term follow-up of diabetic men who survived a first myocardial infarction [68]. Only a trend towards a higher mortality among patients treated with sulfonylureas compared to those on insulin (IDDM an NIDDM) was found [68]. The interpretation of the results concerning the subgroups mentioned above is hampered by the small number of patients and the lack of sufficient data on clinical variables, such as metabolic control, infarction size and concomitant treatment.

The discovery of the mode of action of sulfonylureas (blockade of pancreatic B-cell K.ATP channel) and of the presence of K.ATP channels in the heart and vascular tissue eventually gave rise to new discussions on the clinical implications of the use of these agents in cardiovascular patients [15–17]. These discussions were largely based on experimental data showing significant interaction of sulfonylureas with the cardiovascular system. Most of these, predominantly negative, data have been reviewed by Smits and Thien [17]and by Leibowitz and Cerasi [15]and will not be repeated here. We will focus on studies evaluating the (direct) cardiovascular effects of sulfonylureas in man. In reviewing these data the principle interest is not whether the sulfonylurea-related effects are mediated by K.ATP channel block or not. As argued by Smits and Thien [17], plasma sulfonylurea concentrations in man on chronic treatment may well be sufficient to block vascular and cardiac K.ATP channels.

	6 Direct cardiovascular effects of sulphonylureas in man

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
6.1 Vascular tone
Whereas in different experimental models sulfonylureas have been shown to interfere with coronary vascular smooth muscle relaxation, there are no such data in man. In a study by Nahser el al. [69], evaluating maximal coronary flow reserve and metabolic coronary vasodilation in diabetic and non-diabetic patients, no difference was found between diabetic patients on insulin treatment and those on sulfonylurea derivatives. This study, however, was not designed to investigate the effects of these agents on coronary flow characteristics. Furthermore, on the day of the experiment oral hypoglycemic agents were withheld, probably resulting in serum levels too low to elicit any effect.

More data are available on the peripheral vascular effects of sulfonylureas in man. The acute effects of glibenclamide on baseline flow and hyperemic response to arterial occlusion in the human calf were studied recently [70]. After oral ingestion of 7.5 mg glibenclamide there was a significant decline in baseline flow (30 and 42% of control value after 1 and 2 h) and in peak reactive flow (22, 30 and 28% of control value after 1, 2 and 3 h), and an increase in the duration of the hyperemic response after 2 and 3 h. Total reactive hyperemic volume was not significantly influenced by glibenclamide. Placebo did not cause significant changes in any of these parameters [70]. In another study it was demonstrated that the vasodilator effect of diazoxide was significantly reduced by concomitant infusion of glibenclamide [71]. An important finding in these two studies is the fact that glibenclamide is able to elicit measurable vascular effects at therapeutic serum levels (250 ng/ml=0.5 µM) [19, 72]. Taking into account the high degree of binding to serum albumin (>99%) [73], the serum levels of free glibenclamide in these studies were lower than the threshold value for inhibition of the effect of potassium channel openers on vascular activity (25 ng/ml=0.05 µM) in the experimental model [74]. These findings [70, 71]might have clinical implications for NIDDM patients with coronary disease treated with sulfonylureas. However, it should be emphasized that these studies dealt with healthy volunteers and that there might be different sensitivities for glibenclamide in coronary and peripheral smooth muscle K-ATP channel receptors. In addition, by design only the acute effects of the drugs were investigated, but it has been demonstrated that glibenclamide induced an increase of the relative changes in systemic vascular resistance index also after 4 weeks of treatment whereas metformin, a biguanide, unrelated to sulfonylureas, had no effect [75].

6.2 Myocardial ischemia and preconditioning
Although the effect of sulfonylureas at therapeutic levels on the human coronary vasculature remains to be determined, some evidence that human myocardium is sensitive to such levels of glibenclamide already exists. The oral administration of 10 mg glibenclamide, prior to the procedure, abolished the attenuation of ST-segment shift at a second balloon inflation during coronary angioplasty [76]. Inhibition of collateral circulation recruitment by glibenclamide as a possible explanation for this finding was very unlikely (based on angiographic assessment), suggesting a direct myocardial effect of glibenclamide on ischemic preconditioning. Also in an in vitro model using right atrial trabeculae glibenclamide prevented ‘ischemic’ preconditioning [77]. Since preconditioning is thought to protect the myocardium against subsequent ischemic events, resulting in less extensive myocardial infarction and better clinical outcome [78, 79], the use of glibenclamide might have deleterious effects in patients with repetitive myocardial ischemia treated with this agent.

6.3 Arrhythmias
In various experimental models of acute ischemia pretreatment with sulfonylureas proved antiarrhythmic during myocardial ischemia [16]. Clinical data seem to corroborate these results. In a randomized crossover study in NIDDM (glibenclamide versus metformin), glibenclamide significantly reduced the incidence of ventricular premature complexes and ventricular tachycardia during (spontaneous) transient myocardial ischemia [80]. Glibenclamide did not alter the ischemic burden nor did it interfere with non-ischemia-related arrhythmias [80]. In a study on NIDDM patients suffering from acute myocardial infarction, ventricular fibrillation (VF) occurred significantly less frequently in the glibenclamide-treated group than in NIDDM patients treated otherwise and than in non-diabetics (1.7 vs 7.9 and 9.9%, respectively) [81]. Although demographic, clinical and treatment parameters were comparable in the three groups, there was a much higher mortality rate in the non-glibenclamide treated diabetic patients, which was related to the higher incidence of heart failure in this group [81]. This finding suggests the presence of an unknown confounder, prompting cautious interpretation of the data from this study. On the other hand, recently presented data from a large retrospective study on patients with acute myocardial infarction, similarly showed that the rate of VF in patients on glibenclamide was lower than that for diabetics on gliclazide or insulin [82]. In this study, in contrast to the former study [81], VF rate was the same as that of non-diabetics [82].

Studies involving first-generation sulfonylureas in diabetics with an acute myocardial infarction provided variable results. A trend towards a higher incidence of early VF was shown in diabetics on oral treatment (mainly sulfonylureas), as compared to those treated with insulin or diet alone (12 vs 3 and 7%, respectively) [83]. In a similar study comparing these three groups no difference in primary VF incidence was observed at all [84]. In both studies time from onset of symptoms to hospital admission, a critical factor when it comes to the incidence of primary VF, was however not reported.

6.4 Other effects
Some investigators reported a positive inotropic effect of sulfonylureas [85, 86], whereas others failed to confirm this finding [87, 88]. In vitro studies showed evidence for beneficial effects of certain sulfonylurea derivatives on cardiovascular risk factors such as platelet aggregation and fibrinolysis [15, 66]. However, the clinical relevance of these effects is unclear.

	7 Summary

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 
In summary, the most consistent finding concerning the cardiac effects of sulfonylurea derivatives in NIDDM with ischemic heart disease is the lower incidence of ventricular arrhythmia associated with the use of glibenclamide, while no excess mortality has been shown for this agent. The effect of blockade of myocardial preconditioning by this agent has still to be evaluated with respect to clinical end-points. It should be noted that in the older studies an excess of cardiovascular mortality in diabetics using sulfonylureas was an inconsistent finding and that in those studies virtually only first-generation agents were used. Furthermore, the findings of those studies might not be applicable to current clinical practice. Based on the direct effects described above there are, at present, no firm clinical data on the basis of which sulfonylurea derivatives should be withheld from the cardiac patient.

Time for primary review 29 days.

	Acknowledgements

 
Dr. A.A.M. Wilde is a clinical investigator for the Dutch Heart Foundation (NHS grant D95/014).

	References

Top Abstract 1 Introduction 2 Effects on membrane... 3 Effects on myocardial... 4 Impact on sulfonylurea... 5 NIDDM, sulfonylurea... 6 Direct cardiovascular effects... 7 Summary References

 

1. Aquilar-Bryan L, Nichols CG, Wechsler SW, et al. Cloning of the β cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995;268:423–426.
2. Inagaki N, Gonoi T, Clement IV JP, et al. Reconstitution of I_KATP: an inward rectifier subunit plus the sulphonylurea receptor. Science 1995;270:1166–1170.
3. Inoue I, Nagase H, Kishi K, Higuti T. ATP-sensitive K⁺ channel in the mitochondrial inner membrane. Nature 1991;352:244–247.
4. Paucek P, Miranova G, Mahdi F, Beavis AD, Woldegiorgis G, Garlid KD. Reconstitution and partial purification of the glibenclamide-sensitive, ATP-dependent K⁺ channel from rat liver and beef heart mitochondria. J Biol Chem 1992;267:26062–26069.
5. Garlid KD, Paucek P, Yarov-Yarovoy V, Sun X, Schindler PA. The mitochondrial K_ATP channel as a receptor for potassium channel openers. J Biol Chem 1996;271:8796–8799.
6. Inagaki N, Gonoi T, Clement IV JP, et al. A family of sulphonylurea receptors determines the pharmacological properties of ATP-sensitive K⁺ channels. Neuron 1996;16:1011–1017.
7. Chutkow WA, Simon C, Le Beau M, Burant CF. Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 1996;45:1439–1445.
8. Isomoto S, Kondo C, Yamada M, et al. A novel sulphonylurea receptor form with BIR (Kir 6.2) a smooth muscle type ATP-sensitive K⁺ channel. J Biol Chem 1996;271:24321–24324.
9. Quayle JM, Standen NB. K.ATP channels in vascular smooth muscle. Cardiovasc Res 1994;28:797–804.
10. Hearse DJ. Activation of ATP-sensitive potassium channels: a novel pharmacological approach to myocardial protection? Cardiovasc Res 1995;30:1–17.
11. Cole WC, McPherson CD, Sontag D. ATP regulated K⁺ channels protect the myocardium against ischemia/reperfusion damage. Circ Res 1991;69:571–581.
12. Mitani A, Kinoshita K, Fukamachi K, et al. Effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion. Am J Physiol 1991;261:H1864–H1871.
13. Auchampach JA, Maruyama M, Cavero I, Gross GJ. The new K⁺ channel opener aprikalim (RP 52891) reduces experimental infarct size in dogs in the absence of hemodynamic changes. J Pharmacol Exp Ther 1991;259:961–967.
14. Auchampach JA, Maruyama M, Cavero I, Gross GJ. Pharmacological evidence for a role of ATP-dependent potassium channels in myocardial stunning. Circulation 1992;86:311–319.
15. Leibowitz G, Cerasi E. Sulphonylurea treatment in NIDDM patients with cardiovascular disease: a mixed blessing. Diabetologica 1996;39:503–514.
16. Wilde AAM, Janse MJ. Electrophysiological effects of ATP-sensitive potassium channel modulation: implications for arrhythmogenesis. Cardiovasc Res 1994;28:16–24.
17. Smits P, Thien T. Cardiovascular effects of sulphonylurea derivatives. Implications for the treatment of NIDDM. Diabetologica 1995;38:116–121.
18. Zunckler BJ, Lenzen S, Manner K, et al. Concentration-dependent effects of tolbutamide, meglitinide, glipizide, glibenclamide, and diazoxide on ATP-regulated K⁺ currents in pancreatic β-cells. Naunyn-Schmiedebergs Arch Pharmacol 1988;337:225–230.
19. Sartor G, Melander A, Scherstén B, Wåhlin-Boll E. Serum glibenclamide in diabetic patients, and influence of food on the kinetics and effects of glibenclamide. Diabetologia 1980;18:17–22.
20. Venkatesh N, Lamp ST, Weiss JN. Sulphonylureas, ATP-sensitive K⁺ channels, and cellular K⁺ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle. Circ Res 1991;69:623–637.
21. Ripoll C, Lederer J, Nichols CG. On the mechanism of inhibition of K_ATP channels by glibenclamide in rat ventricular myocytes. J Cardiovasc Electrophysiol 1993;438–447.
22. Findlay I. Inhibition of ATP-sensitive K⁺ channels in cardiac muscle by the sulphonylurea drug glibenclamide. J Pharmacol Exp Ther 1992;261:540–545.
23. Schmid-Antomarchi H, De Weille J, Fosset M, Lazdunski M. The receptor for antidiabetic sulfonylureas controls the activity of the ATP-modulated K⁺ channel in insulin-secreting cells. J Biol Chem 1987;262:15840–15844.
24. Sturgess NC, Kozlowski RZ, Carrington CA, et al. Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide-sensitive channels in an insulin-secreting cell line. Br J Pharmacol 1988;95:83–94.
25. Findlay I. Effects of pH upon the inhibition by sulphonylurea drugs of ATP-sensitive K⁺ channels in cardiac muscle. J Pharmacol Exp Ther 1992;262:71–79.
26. Findlay I. Sulphonylurea drugs no longer inhibit ATP-sensitive K⁺ channels during metabolic stress in cardiac muscle. J Pharmacol Exp Ther 1993;266:456–467.
27. Tominaga M, Horie M, Sasayama S, Okada Y. Glibenclamide, an ATP-sensitive K⁺ channel blocker, inhibits cAMP-activated Cl^– conductance. Circ Res 1995;77:417–423.
28. Sheppard DN, Welsch MJ. Effect of ATP-sensitive K⁺ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents. J Gen Physiol 1992;100:573–591.
29. Trube G, Rorsman P, Ohno-Shosaku T. Opposite effects of tolbutamide and diazoxide on the ATP dependent K⁺ channel in mouse pancreatic β-cells. Pflügers Arch 1986;407:493–499.
30. Reeve HL, Vaughan PFT, Peers C. Glibenclamide inhibits a voltage-gated K⁺ current in the human neuroblastoma cell line SH-SY5Y. Neurosci Lett 1992;135:37–40.
31. Bian K, Hermsmeyer K. Glyburide actions on the dihydropyridine-sensitive Ca²⁺ channel in rat vascular muscle. J Vasc Res 1994;31:256–264.
32. Gelband CH, McCullough JR, van Breemen C. Modulation of vascular Ca²⁺-activated K⁺ channels by cromakalim, pinacidil and glyburide. Biophys J 1990;57:509a(Abstract).
33. Xiong Z, Kajioka S, Sakai T, et al. Pinacidil inhibits the ryanodine-sensitive outward current and glibenclamide antagonizes its action in cells from the rabbit portal vein. Br J Pharmacol 1991;102:788–790.
34. Chopra LC, Twort CHC, Ward JPT. Direct action of BRL 38227 and glibenclamide on intracellular calcium stores in cultured airway smooth muscle of rabbit. Br J Pharmacol 1992;105:259–260.
35. Fink RHA, Stephenson DG. Ca²⁺ movements in muscle modulated by the state of K⁺ channels in the sarcoplasmatic reticulum membranes. Pflügers Arch 1987;409:374–380.
36. Kramer JH, Lampson WG, Schaffer SW. Effect of tolbutamide on myocardial energy metabolism. Am J Physiol 1983;245:H313–H319.
37. Tan BH, Wilson GL, Schaffer SW. Effect of tolbutamide on myocardial metabolism and mechanical performance of the diabetic rat. Diabetes 1984;33:1138–1143.
38. Cook GA. The hypoglycemic sulphonylureas glyburide and tolbutamide inhibit fatty acid oxidation by inhibiting carnitine palmitoyl-transferase. J Biol Chem 1987;262:4968–4972.
39. Weiss JN, Lamp ST. Cardiac ATP-sensitive K⁺ channels. Evidence for preferential regulation by glycolysis. J Gen Physiol 1989;94:911–935.
40. Wilde AAM, Escande D, Schumacher CA, et al. Potassium accumulation in the globally ischemic mammalian heart: A role for the ATP-sensitive potassium channel. Circ Res 1990;67:835–843.
41. Gwilt M, Norton B, Henderson CG. Pharmacological studies of K⁺ loss from ischaemic myocardium in vitro: roles of ATP-dependent K⁺ channels and lactate-coupled efflux. Eur J Pharmacol 1993;236:107–112.
42. Wilde AAM, Aksnes G. Myocardial potassium loss and cell depolarization in ischemia and hypoxia. Cardiovasc Res 1995;29:1–15.
43. Harvey RD, Hume JR. Autonomic regulation of a chloride current in heart. Science 1989;244:983–985.
44. Ruiz Petrich E, Zumino AP, Schanne OF. Early action potential shortening in hypoxic hearts: role of chloride current(s) mediated by catecholamine release. J Mol Cell Cardiol 1996;28:279–290.
45. Benndorf K, Friedrich M, Hirche Hj. Anoxia opens ATP regulated K channels in isolated heart cells of the guinea pig. Pflügers Arch 1991;419:108–110.
46. Henry P, Popescu A, Pucéat M, Hinescu ME, Escande D. Acute simulated ischaemia produces both inhibition and activation of K⁺ currents in isolated ventricular myocytes. Cardiovasc Res 1996;32:930–939.
47. Veldkamp MW, van Ginneken ACG, Opthof T, Wilde AAM, Bouman LN. Metabolic inhibition induced action potential shortening coincides with an increase in whole-cell outward current, but not with the opening of single K.ATP channels in the patch membrane. Submitted 1996.
48. Yan GX, Yamada KA, Kléber AG, McHowat J, Corr PB. Dissociation between cellular K⁺ loss, reduction in repolarization time, and tissue ATP levels during myocardial hypoxia and ischemia. Circ Res 1993;72:560–570.
49. Cascio WE, Yan G, Kléber AG. Early changes in extracellular potassium in ischemic rabbit myocardium. The role of extracellular carbon dioxide accumulation and diffusion. Circ Res 1992;70:409–422.
50. Schaffer S, Carr LJ, Prussel E, Ramasamy R. Effects of glycogen depletion on ischemic injury in isolated rat hearts: insights into preconditioning. Am J Physiol 1995;268:H935–H944.
51. Cross HR, Opie LH, Radda GK, Clarke K. Is a high glycogen content beneficial or detrimental to the ischemic rat heart? Circ Res 1996;78:482–491.
52. Wissner SB. The effect of excess lactate upon the excitability of the sheep Purkinje fiber. J Electrocardiol 1974;7:17–26.
53. Keung EC, Li Q. Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes. J Clin Invest 1991;88:1772–1777.
54. Wolfe CL, Sievers RE, Visseren FJL, Donelly TJ. Loss of myocardial protection after preconditioning correlates with the time course of glycogen recovery within the preconditioned segment. Circulation 1993;87:881–892.
55. Cohen MV, Snell KS, Tsuchida A, van Wylen DGL, Downey JM. Effects of anesthesia and K⁺ ATP channel blockade on interstitial adenosine accumulation in ischemic rabbit myocardium. Basic Res Cardiol 1995;90:410–417.
56. Sato T, Obata T, Yamanaka Y, Arita M. Glibenclamide decreases adenosine production in rat hearts by inhibiting 5'-nucleotidase. Circulation 1996;94(suppl I):I-364(Abstract).
57. Kitakaze M, Hori M, Morioka T, et al. Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5'-nucleotidase activity and attenuation of adenosine release. Circulation 1994;89:1237–1246.
58. Sanquinetti MC. Modulation of potassium channels by antiarrhythmic and antihypertensive drugs. Hypertension 1992;19:228–236.
59. Garcia MJ, McNamara PM, Gordon T, Kannell WB. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes 1974;23:105–111.
60. Rytter L, Troelsen S, Beck-Nielsen H. Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care 1985;8:230–234.
61. Groop LC. Sulphonylureas in NIDDM. Diabetes Care 1992;15:737–754.
62. Anonymous. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results: University Group Diabetes Program. Diabetes 1970;19(suppl 2):747–830.
63. Seltzer HS. A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP). Diabetes 1972;21:976–979.
64. Feinstein AR. Clinical biostatistics. XXXV. The persistent clinical failures and fallacies of the UGPD study. Clin Pharmacol Ther 1976;19:78–93.
65. Kilo C, Miller JP, Williamson JR. The Achilles heel of the University Group Diabetes Program. J Am Med Assoc 1980;243:450–457.
66. Huupponen R. Adverse cardiovascular effects of sulphonylurea drugs. Clinical significance. Med Toxicol 1987;2:190–209.
67. Yudkin JS, Oswald GA. Determinants of hospital admission and case fatality in diabetic patients with myocardial infarction. Diabetes Care 1988;11:351–358.
68. Ulvenstam G, Åberg A, Bergstrand R, et al. Long-term prognosis after myocardial infarction in men with diabetes. Diabetes 1985;34:787–792.
69. Nahser PJ, Brown RE, Oskarsson H, Winniford MD, Rossen JD. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 1995;91:635–640.
70. Kosmas EN, Levy RD, Hussain SNA. Acute effects of glyburide on the regulation of peripheral blood flow in normal humans. Eur J Pharmacol 1995;274:193–199.
71. Bijlstra PJ, Lutterman JA, Russell FGM, Thien T, Smits P. Interaction of sulphonylurea derivatives with vascular ATP sensitive channels in humans. Diabetologia 1996;39:1083–1090.
72. Groop L, Groop PH, Stenman S, et al. Comparison of pharmacokinetics, metabolic effects and action of glyburide and glipizide during long-term treatment. Diabetes Care 1987;10:671–678.
73. Crooks MJ, Brown KF. The binding of sulphonylureas to serum albumin. J Pharm Pharmacol 1974;26:304–311.
74. Meisheri KD, Khan SA, Martin JL. Vascular pharmacology of vascular K⁺ channels: interactions between glyburide and potassium channel openers. J Vasc Res 1993;30:2–12.
75. Chan JCN, Tomlinson B, Critchley JAJH, Cockram CS, Walden RJ. Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. Diabetes Care 1993;16:1035–1038.
76. Tomai F, Crea F, Gaspardone A, et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K⁺ channel blocker. Circulation 1994;90:700–705.
77. Speechly-Dick ME, Grover GJ, Yellon DM. Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K⁺ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model. Circ Res 1995;77:1030–1035.
78. Kloner RA, Shook T, Przyklenk K, et al. Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation 1995;91:37–47.
79. Ottani F, Galvani M, Ferrini D, et al. Prodromal angina limits infarct size. A role for ischemic preconditioning. Circulation 1995;91:291–297.
80. Cacciapuoti F, Spiezia R, Bianchi U et al. Effectiveness of glibenclamide on myocardial ischemic ventricular arrhythmias in non-insulin-dependent diabetes mellitus. Am J Cardiol 1991;67:843–847.
81. Lomuscio A, Vergani D, Marano L, Castagnone M, Fiorentini C. Effects of glibenclamide on ventricular fibrillation in non-insulin-dependent diabetics with acute myocardial infarction. Coron Artery Dis 1994;5:767–771.
82. Davis TME, Parsons RW, Broadhurst R, Hobbs M, Jamrozik K. Arrhythmias and mortality after myocardial infarction in diabetic patients: relationship to diabetes treatment. Diabetologia 1996;39(suppl 1):A51(Abstract).
83. Soler NG, Pentecost BL, Bennett MA, et al. Coronary care for myocardial infarction in diabetics. Lancet 1974;1:475–477.
84. Lichstein E, Kuhn LA, Goldburg E, et al. Diabetic treatment and primary ventricular fibrillation in acute myocardial infarction. Am J Cardiol 1976;38:100–102.
85. Rothschild MA, Rothschild AH, Pfeifer MA. The inotropic action of tolbutamide and glyburide. Clin Pharmacol Ther 1989;45:642–649.
86. Hildner FJ, Yeh BK, Javier RP, Fester A, Samet P. Inotropic action of tolbutamide on human myocardium. Cathet Cardiovasc Diagn 1975;1:47–57.
87. Sykes CA, Wright AD, Malins JM, Pentecost BL. Changes in systolic time intervals during treatment of diabetes mellitus. Br Heart J 1977;39:255–259.
88. Dubach UC, Burckhardt D, Raeder EA, et al. Effect of intravenous glibornuride and tolbutamide on myocardial contractility. Cardiology 1979;64:208–214.

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				T.-M. Lee, M.-S. Lin, and N.-C. Chang Effect of pravastatin on sympathetic reinnervation in postinfarcted rats Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3617 - H3626. [Abstract] [Full Text] [PDF]

				T.-M. Lee, M.-S. Lin, C.-H. Tsai, and N.-C. Chang Effect of pravastatin on left ventricular mass in the two-kidney, one-clip hypertensive rats Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2705 - H2713. [Abstract] [Full Text] [PDF]

				F. Brigadeau, C. Kouakam, D. Klug, C. Marquie, A. Duhamel, F. Mizon-Gerard, D. Lacroix, and S. Kacet Clinical predictors and prognostic significance of electrical storm in patients with implantable cardioverter defibrillators Eur. Heart J., March 2, 2006; 27(6): 700 - 707. [Abstract] [Full Text] [PDF]

				T. Saito, T. Sato, T. Miki, S. Seino, and H. Nakaya Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H352 - H357. [Abstract] [Full Text] [PDF]

				R. M Mohan and D. J Paterson Activation of sulphonylurea-sensitive channels and the NO-cGMP pathway decreases the heart rate response to sympathetic nerve stimulation Cardiovasc Res, July 1, 2000; 47(1): 81 - 89. [Abstract] [Full Text] [PDF]

				C. A. Remme and A. A.M Wilde A new, sympathetic look at KATP channels in the heart Cardiovasc Res, July 1, 1999; 43(1): 17 - 19. [Full Text] [PDF]

				K. Oe, B. Sperlagh, E. Santha, I. Matko, H. Nagashima, F. F Foldes, and E.S. Vizi Modulation of norepinephrine release by ATP-dependent K+-channel activators and inhibitors in guinea-pig and human isolated right atrium Cardiovasc Res, July 1, 1999; 43(1): 125 - 134. [Abstract] [Full Text] [PDF]

				C. E. Schotborgh and A. A.M. Wilde ATP-Sensitive Potassium Channel Openers and Blockers in the Cardiovascular System: Physiology, Pharmacology, and Clinical Effects Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 1998; 2(3): 243 - 255. [Abstract] [PDF]

				F.C Huvers, P.W de Leeuw, C.H.A de Haan, A.J.H.M Houben, C Buijs, and N.C Schaper The enhanced pressor response in type 2 diabetes is not based upon a generalized increase in vascular responsiveness Cardiovasc Res, April 1, 1998; 38(1): 206 - 214. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Schotborgh, C. E Articles by Wilde, A. A.M Search for Related Content PubMed PubMed Citation Articles by Schotborgh, C. E Articles by Wilde, A. A.M Social Bookmarking          What's this?

Online ISSN 1755-3245 - Print ISSN 0008-6363

Copyright © 2010 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics